The combination of modified acupuncture needle and melittin hydrogel as a novel therapeutic approach for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) involves chronic joint inflammation. Combining acupuncture and medication for RA treatment faces challenges like spatiotemporal variability, limited drug loading in acupuncture needles, and premature or untargeted drug release. Here, we designed a new type of tubular acupuncture needles, with an etched hollow honeycomb-like structure to enable the high loading of therapeutics, integrating the traditional acupuncture and drug repository into an all-in-one therapeutic platform. In these proof-of-concept experiments, we fabricated injectable hollow honeycomb electroacupuncture needles (HC-EA) loaded with melittin hydrogel (MLT-Gel), enabling the combination treatment of acupuncture stimulation and melittin therapy in a spatiotemporally synchronous manner. Since the RA microenvironment is mildly acidic, the acid-responsive chitosan (CS)/sodium beta-glycerophosphate (ß-GP)/ hyaluronic acid (HA) composited hydrogel (CS/GP/HA) was utilized to perform acupuncture stimulation and achieve the targeted release of injected therapeutics into the specific lesion site. Testing our therapeutic platform involved a mouse model of RA and bioinformatics analysis. MLT-Gel@HC-EA treatment restored Th17/Treg-mediated immunity balance, reduced inflammatory factor release (TNF-α, IL-6, IL-1ß), and alleviated inflammation at the lesion site. This novel combination of modified acupuncture needle and medication, specifically melittin hydrogel, holds promise as a therapeutic strategy for RA treatment.

Effect of quick acupuncture combined with rehabilitation therapy on improving motor and swallowing function in patients with stroke.

OBJECTIVE: To investigate the effect of quick acupuncture combined with rehabilitation therapy on motor and swallowing function of patients with stroke. DESIGN: A retrospective study. SETTING: Single center study. PARTICIPANTS: One hundred and twenty patients with stroke were divided into control and observation group based on the therapeutic regimen. INTERVENTION: Control group (n = 60) only received rehabilitation therapy, and observation group (n = 60) received rehabilitation therapy combined with quick acupuncture. Acupuncture was performed once a day, and 6 times/week for 4 consecutive weeks. MAIN MEASURES: The simplified Fugl-Meyer assessment scale and Barthel index were used to assess limb motor function and daily living ability. The Dysphagia Outcome Severity Scale and Swallowing Quality of Life questionnaire were conducted to estimate the dysphagia severity and life quality of patients with swallowing disorders. The therapeutic efficacy and complications after treatment were analyzed and counted. RESULTS: After treatment, the scores of the observation group were significantly improved compared with the control group (P < 0.05). In the observation group, the therapeutic efficacy was 93% (n = 56); the complication rate was 5% (n = 3); the therapeutic efficacy of the control group was 75% (n = 45); and the complication rate was 25% (n = 15), indicating that the therapeutic efficacy of the observation group is better and the incidence of complications is lower than that of the control group. CONCLUSION: This study suggests that rehabilitation therapy combined with rapid acupuncture therapy has a potential therapeutic effect on the relief of swallowing and motor dysfunction after stroke.

Causal relationship between Alzheimer's disease and prostate cancer: a bidirectional Mendelian randomization analysis.

Background: Previous observational researchers have found an inverse bidirectional link between Alzheimer's disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted. Methods: This study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran's Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results. Results: The causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables. Conclusion: The results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD.

A tumor targeted nano micelle carrying astragaloside IV for combination treatment of bladder cancer.

Immune checkpoint inhibitors (ICIs) are effective agents for tumor immunotherapy. However, their clinical effectiveness is unsatisfactory due to off-target effects and a suppressive immune microenvironment. This study developed a nanodrug delivery system for bladder cancer (BCa) using PCL-MPEG and PCL-PEG-CHO to synthesize internal hydrophobic and external hydrophilic micelles (PP) that encapsulated water-insoluble astragaloside IV (PPA). The aldehyde group on the surface of PPA reacted with the amino group of aPD-L1, allowing the decoration of this antibody on the surface of the micelles. The resultingPPA@aPD-L1effectively piggybacked astragaloside IV and aPD-L1 antibody. These findings suggest that PPA@aPD-L1 is relatively stable in circulation and efficiently binds to BCa cells with the aid of aPD-L1. Additionally, this strategy prolongs the drug's retention time in tumors. Compared to PBS, PP, and PPA with PPA + aPD-L1 groups, PPA@aPD-L1significantly prolonged the survival of mice with BCa and reduced tumor volume. Mechanistic studies showed that PPA inhibited the NF-κB and STAT3 signaling pathways in tumor cells. Additionally, PPA@aPD-L1increased IFN-γ and decreased IL-10 expression in bladder tumors, affecting the number and type of intratumorally infiltrating T cells. Our study presents a simple and effective drug delivery system that combines herbal monomers with ICIs. It has demonstrated a potent ability to suppress tumor growth and holds potential for future applications.

Comparison of bladder carcinogenesis biomarkers in the urine of traditional cigarette users and e-cigarette users.

Background: During the use of electronic cigarettes (e-cigarettes), users are still exposed to carcinogens similar to those found in tobacco products. Since these carcinogens are metabolized and excreted in urine, they may have carcinogenic effects on the bladder urinary tract epithelium. This meta-analysis aimed to compare bladder cancer carcinogens in the urine of tobacco users and e-cigarette users using a large number of samples. Methods: A systematic meta-analysis was performed using data obtained from several scientific databases (up to November 2023). This cumulative analysis was performed following the Preferred Reporting Items for Systematic Evaluation and Meta-Analysis (PRISMA) and Assessing the Methodological Quality of Systematic Evaluations (AMSTAR) guidelines, according to a protocol registered with PROSPERO. This study was registered on PROSPERO and obtained the unique number: CRD42023455600. Results: The analysis included 10 high-quality studies that considered polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs) and tobacco-specific nitrosamines (TSNAs). Statistical indicators show that there is a difference between the tobacco user group and the e-cigarette user group in terms of 1-Hydroxynaphthalene (1-NAP) [weighted mean difference (WMD)10.14, 95% confidence interval (CI) (8.41 to 11.88), p < 0.05], 1-Hydroxyphenanthrene (1-PHE) [WMD 0.08, 95% CI (-0.14 to 0.31), p > 0.05], 1-Hydroxypyrene (1-PYR) [WMD 0.16, 95% CI (0.12 to 0.20), p < 0.05], 2-Hydroxyfluorene (2-FLU) [WMD 0.69, 95% CI (0.58 to 0.80), p < 0.05], 2-Hydroxynaphthalene (2-NAP) [WMD 7.48, 95% CI (4.15 to 10.80), p < 0.05], 3-Hydroxyfluorene (3-FLU) [WMD 0.57, 95% CI (0.48 to 0.66), p < 0.05], 2-Carbamoylethylmercapturic acid (AAMA) [WMD 66.47, 95% CI (27.49 to 105.46), p < 0.05], 4-Hydroxy-2-buten-1-yl-mercapturic acid (MHBMA) [WMD 287.79, 95% CI (-54.47 to 630.04), p > 0.05], 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNAL) [WMD 189.37, 95% CI (78.45 to 300.29), p < 0.05], or N0-nitrosonornicotine (NNN) [WMD 11.66, 95% CI (7.32 to 16.00), p < 0.05]. Conclusion: Urinary bladder cancer markers were significantly higher in traditional tobacco users than in e-cigarette users.Systematic review registration: PROSPERO (CRD42023455600: https://www.crd.york.ac.uk/PROSPERO/).

Assessing the role of statin therapy in bladder cancer: evidence from a Mendelian Randomization study.

Background: Statins, which are medications that lower lipid levels, are extensively used to decrease cardiovascular disease risk. Recently, the use of statins in cancer prevention has attracted considerable interest. However, it is still unclear whether the use of statins has a causal effect on bladder cancer. Methods: The two-sample Mendelian Randomization (MR) was performed to infer the causal relationship between statin therapy (atorvastatin, simvastatin, and rosuvastatin) and bladder cancer. Single-nucleotide polymorphisms (SNP)-based genome-wide association studies (GWAS) of statins (atorvastatin, simvastatin, and rosuvastatin) were gathered from the UK Biobank, involving 462,933 participants. We acquired summary-level genetic data on bladder cancer from a European cohort of 175,121 individuals. The inverse variance weighted (IVW) method was the main analytical technique used, supplemented by MR-Egger, weighted median, weighted mode, and simple mode to estimate causal effects. Additionally, sensitivity analyses were conducted to verify the robustness and reliability of our findings. Results: Based on the IVW analysis, we identified a significant causal association between rosuvastatin use and a decreased risk of bladder cancer, with genetic analysis inferring the substantial reduction in odds (OR = 3.52E-19, 95% CI: 5.48E-32-2.26E-06, p = 0.005). In contrast, the IVW results did not reveal a statistically significant relationship between the genetically estimated use of atorvastatin (OR = 7.42E-03, 95% CI: 6.80E-06-8.084, p = 0.169) or simvastatin (OR = 0.135, 95% CI: 0.008-2.330, p = 0.168) and bladder cancer risk. Conclusion: We investigated the causal link between statin therapy (atorvastatin, simvastatin, and rosuvastatin) and bladder cancer using a two-sample Mendelian Randomization analysis among the European population. Our findings indicated that genetically predicted use of rosuvastatin was associated with a decreased risk of bladder cancer, whereas no significant genetically predicted causal effects were observed for atorvastatin and simvastatin use.

Synergistic intravesical instillation for bladder cancer: CRISPR-Cas13a and fenbendazole combination therapy.

BACKGROUND: CRISPR-Cas13a is renowned for its precise and potent RNA editing capabilities in cancer therapy. While various material systems have demonstrated efficacy in supporting CRISPR-Cas13a to execute cellular functions in vitro efficiently and specifically, the development of CRISPR-Cas13a-based therapeutic agents for intravesical instillation in bladder cancer (BCa) remains unexplored. METHODS: In this study, we introduce a CRISPR-Cas13a nanoplatform, which effectively inhibits PDL1 expression following intravesical instillation. This system utilizes a fusion protein CAST, created through the genetic fusion of CRISPR-Cas13 and the transmembrane peptide TAT. CAST acts as a potent transmembrane RNA editor and is assembled with the transepithelial delivery carrier fluorinated chitosan (FCS). Upon intravesical administration into the bladder, the CAST-crRNAa/FCS nanoparticles (NPs) exhibit remarkable transepithelial capabilities, significantly suppressing PDL1 expression in tumor tissues.To augment immune activation within the tumor microenvironment, we integrated a fenbendazole (FBZ) intravesical system (FBZ@BSA/FCS NPs). This system is formulated through BSA encapsulation followed by FCS coating, positioning FBZ as a powerful chemo-immunological agent. RESULTS: In an orthotropic BCa model, the FBZ@BSA/FCS NPs demonstrated pronounced tumor cell apoptosis, synergistically reduced PDL1 expression, and restructured the immune microenvironment. This culminated in an enhanced synergistic intravesical instillation approach for BCa. Consequently, our study unveils a novel RNA editor nanoagent formulation and proposes a potential synergistic therapeutic strategy. This approach significantly bolsters therapeutic efficacy, holding promise for the clinical translation of CRISPR-Cas13-based cancer perfusion treatments.

A Dopamine-Modified Hyaluronic Acid-Based Mucus Carrying Phytoestrogen and Urinary Exosome for Thin Endometrium Repair.

Thin endometrium (TE) is closely associated with infertility in reproductive medicine. Estrogen therapy gains unsatisfactory outcomes. In this study, an artificial mucus based on dopamine (L-DOPA)-modified hyaluronic acid combining phytoestrogen cajaninstilbene acid and rat urinary exosomes (CUEHD) is constructed for TE treatment using a rat TE model. In the rat TE model, the dominant elastic behavior and adhesive properties of CUEHD guarantee adequate retention, rendering superior synergistic treatment efficacy and favorable biosafety characteristics. CUEHD treatment significantly increases endometrial thickness and promotes receptivity and fertility. Mechanistically, estrogen homeostasis, inflammation inhibition, and endometrial regeneration are achieved through the crosstalk between ER-NLRP3-IL1ß and Wnt-ß catenin-TGFß-smad signaling pathways. Moreover, the therapeutic potential of exosomes from human urine and adipose tissue-derived stem cells (ADSCs) and rat ADSCs are also demonstrated, indicating extensive use of the artificial mucus system. Thus, this study illustrates a platform combining phytoestrogen and exosomes with promising implications for TE treatment.

Potential causal association between aspirin use and erectile dysfunction in European population: a Mendelian randomization study.

Background: Aspirin, as one of the most commonly used drugs, possesses a broad spectrum of therapeutic applications. Presently, the potential association between aspirin usage and the risk elevation of erectile dysfunction (ED) remains inconclusive. The objective of this study employing two-sample Mendelian randomization (MR) was to clarify the causal impact of aspirin use on the risk of ED. Methods: This study incorporated two sets of Genome-Wide Association Study (GWAS) summary statistics, one for aspirin use (46,946 cases and 286,635 controls) and another for ED (6,175 cases and 217,630 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode to estimate the causal effect of aspirin usage on the risk of ED development. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran's Q test was adopted to check heterogeneity, and the leave-one-out analysis was performed to confirm the robustness and reliability of the results. Results: The causal association between genetically inferred aspirin use and ED was found by using inverse variance weighted (OR = 20.896, 95% confidence interval = 2.077-2.102E+2, P = 0.010). The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. Furthermore, the leave-one-out analysis demonstrated that the findings were not significantly affected by any instrumental variables. Conclusion: The results of this study highlighted the significance of aspirin use as a predisposing factor for ED and provided further evidence supporting the causal association between aspirin utilization and ED within European populations.